Periodic Reporting for period 3 - Respiratory-ImmunoDx (Clinical validation of host biomarker signature for distinguishing bacterial versus viral lower respiratory tract infections (LRTI) in adults at the point-of-need) Reporting period: 2017-12-01 to 2018-11-30 Summary of the context and overall objectives of the project Lower respiratory tract infection (LRTI), primarily pneumonia and bronchitis, is the third leading cause of death worldwide. The incidence of LRTIs in Europe is 30 million, greater than diabetes mellitus (2 million) and malignant neoplasms (2.4 million) combined leading to 230,000 deaths, and over 1 million hospitalizations. The attendant economic burden of LRTI in Europe is estimated at €46 billion annually (direct and indirect costs). LRTI presents a diagnostic challenge due to the difficulty in pathogen sampling and the often indistinguishable clinical symptoms of bacterial and viral etiologies. This uncertainty leads to antibiotic misuse, both overuse (typically for bronchitis) and underuse (often for community-acquired pneumonia, CAP). Overuse of antibiotics may expose the patient to unnecessary adverse side effects and contributes to emergence of antimicrobial resistance, currently a major global health threat. Underuse may cause the patient to suffer prolonged disease and increases the likelihood of hospitalization and mortality, with attendant health and economic costs. In the case of CAP, late treatment with antibiotics has been shown to directly impact mortality. Older adults are at risk for LRTIs due to immunosenescence and co-morbidities, as reflected by increasing incidence with age. In view of the aging European population, the human and economic burden of LRTI is predicted to increase in the coming years. Since most adult LRTIs are managed on an outpatient basis, innovative approaches are warranted that will provide the clinician with actionable information at the point-of-need (community clinic and emergency department [ED]) – to treat or not to treat with antimicrobial therapy – with the goal of promoting 'healthy aging'.Today, LRTI patient management at the point-of-need is guided mainly by clinical symptoms, and in some cases, by the circulating levels of biomarkers. However, the diagnostic performance of each biomarker alone is often restricted. Furthermore, as all these biomarkers are predominantly bacterially-induced, their combination leads to limited diagnostic improvement.To address this, MeMed has previously identified a three host-biomarker signature that comprises a novel viral induced protein called TRAIL, which at that time was not in clinical use. Based on this proprietary biomarker signature, MeMed developed and received EU regulatory approval (CE-IVD) for a diagnostic test called ImmunoXpert™. This test uses microplates to measure serum levels of the three proteins (TRAIL, IP-10 and CRP) and applies proprietary software to integrate their values and generate viral and bacterial likelihood scores. In a prospective clinical study with over 1000 patients MeMed demonstrated that ImmunoXpert™ accurately distinguished viral versus bacterial acute infections across different group ages, physiological systems (e.g. upper respiratory, urinal and gastrointestinal) and a broad range of pathogens (56 strains), significantly outperforming traditional tests. Two main objectives were pursued as part of this project with the aim of facilitating wide adoption of the ImmunoXpert™ test for managing LRTI adult patients at the point-of-need: Objective (1): To clinically validate the biomarker signature for accurate diagnosis of viral versus bacterial LRTI, in a multi-center, prospective pan-European study enrolling adults in EDs and clinics.Objective (2): To develop, validate and prepare for EU regulatory clearance for a new point-of-need device, that will allow rapid measurements (15 minutes) of the signature and is compatible with serum and whole blood samples. Work performed from the beginning of the project to the end of the period covered by the report and main results achieved so far Towards Objective 1, we have successfully completed a prospective, multicenter validation study of the TRAIL/IP-10/CRP signature in adults with suspicion of LRTI (NCT03011515). Data analysis of this OBSERVER study indicates ImmunoXpert™ exhibited sensitivity and specificity greater than 90%. These data support high performance of the signature in adults with suspicion of LRTI and were presented at 29th European Congress of Clinical Microbiology & Infectious Diseases (ECCMID). Towards Objective 2, we have successfully developed and produced a point-of-need diagnostic system (compact reader and disposable cartridge compatible with serum and whole blood samples) that can measure the TRAIL/IP-10/CRP signature in 15 minutes on serum samples with high precision. The diagnostic system has been designed and developed to comply with EU regulatory requirements. Additionally, during the period of the action, MeMed has executed a rigorous branding process. The diagnostic reader is now branded as MeMed Key™ and the host-signature for distinguishing between bacterial and viral infections (TRAIL/IP-10/CRP) is now branded as MeMed BV™. MeMed’s website was redone to support this branding process. We have published 8 Press Releases about MeMed's achievements, which prompted many articles in the industry press. We presented about our POC platform and TRAIL/IP-10/CRP test at multiple academic and industry conferences, either MeMed representatives or representatives of our collaborators.We have also joined various initiatives towards tackling antimicrobial resistance (AMR), including the ‘CDC AMR Challenge’ and the BEAM Alliance, a network of approx. 50 small and medium-sized European biopharmaceutical companies committed to tackling AMR. In addition, during the period of the action, we have expanded our network of key opinion leaders across Europe and the US, as we are laying the groundwork for launch of MeMed BV™ on Key™. Progress beyond the state of the art and expected potential impact (including the socio-economic impact and the wider societal implications of the project so far) Attainment of the project's two synergistic objectives is highly aligned with the goals of the Horizon 2020 SME instrument and MeMed’s business strategy, and will allow a pioneering product to achieve accelerated market adoption, initially in Europe and then globally. The validated TRAIL/IP-10/CRP signature (MeMed BV™), measured using the new diagnostic system (Key™), will give physicians, simple, accurate, and actionable information to improve the management of LRTI adult patients, at the place and time where it is most needed. This tool has the potential to profoundly impact the quality of life for patients by reducing adverse effects due to antibiotic overuse and also, by reducing complications and mortality due to underuse. More generally, MeMed BV™ on Key™ is anticipated to help reverse the trend of increasing hospitalization and its associated economic burden, and on the societal level, to slow the emergence of antibiotic resistant bacteria – one of today's major public health threats.